• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8177-8182
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• 2014

Background: Blocking angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling pathway to inhibit tumor growth has proven to be successful in treating a variety of different metastatic tumor types, including kidney, colon, ovarian, and lung cancers, but its role in castration-resistant prostate cancer (CRPC) is still unknown. We here aimed to determine the efficacy and toxicities of anti-VEGF agents in patients with CRPC. Materials and Methods: The databases of PubMed, Web of Science and abstracts presented at the American Society of Clinical Oncology up to March 31, 2014 were searched for relevant articles. Pooled estimates of the objective response rate (ORR) and prostate-specific antigen (PSA) response rate (decline ${\geq}50%$) were calculated using the Comprehensive Meta-Analysis (version 2.2.064) software. Median weighted progression-free survival (PFS) and overall survival (OS) time for anti-VEGF monotherapy and anti-VEGF-based doublets were compared by two-sided Student's t test. Results: A total of 3,841 patients from 19 prospective studies (4 randomized controlled trials and 15 prospective nonrandomized cohort studies) were included for analysis. The pooled ORR was 12.4% with a higher response rate of 26.4% (95%CI, 13.6-44.9%) for anti-VEGF-based combinations vs. 6.7% (95%CI, 3.5-12.7%) for anti-VEGF alone (p=0.004). Similarly, the pooled PSA response rate was 32.4% with a higher PSA response rate of 52.8% (95%CI: 40.2-65.1%) for anti-VEGF-based combinations vs. 7.3% (95%CI, 3.6-14.2%) for anti-VEGF alone (p<0.001). Median PFS and OS were 6.9 and 22.1 months with weighted median PFS of 5.6 vs. 6.9 months (p<0.001) and weighted median OS of 13.1 vs. 22.1 months (p<0.001) for anti-VEGF monotherapy vs. anti-VEGF-based doublets. Conclusions: With available evidence, this pooled analysis indicates that anti-VEGF monotherapy has a modest effect in patients with CRPC, and clinical benefits gained from anti-VEGF-based doublets appear greater than anti-VEGF monotherapy.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3503-3507
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• 2013

Background: Although the majority of investigations concerned with TP53 and its protein have focused on coding regions, recently a set of studies highlighted significant roles of regulatory elements located in p53 mRNA, especially 5'UTR. The wrap53${\alpha}$ transcript is one of those that acts as a natural antisense agent, forming RNA-RNA hybrids with p53 mRNA and protecting it from degradation. Materials and Methods: In this study, we focused on the mutation status of exon $1{\alpha}$ of the WRAP53 gene (according to exon 1 of p53) in 160 breast tumor tissue samples and conducted a bioinformatics search for probable miRNA binding site in the p53/wrap53 overlapping region. Mutations were detected, using single stranded conformation polymorphism (SSCP) and sequencing. We applied the miRBase database for prediction of miRNAs which target overlapping region of p53/wrap53 transcripts. Results: Our results showed all samples to have wild type alleles in exon 1 of TP53 gene. We could detect a novel and unreported intronic mutation (IVS1+56, G>C) outside overlapping regions of p53/wrap53 genes in breast cancer tissues and also predict the presence of a binding site for miR-4732-5p in the 5'UTR of Wrap53 mRNA. Conclusions: From our findings we propose designing further studies focused on overexpression of miRNA-4732-5p and introducing different mutations in the overlapping region of wrap53 and p53 genes in order to study their effects on p53 and its ${\Delta}N$ isoform (${\Delta}$40p53) expression. The results may provide new pieces in the p53 targeting puzzle for cancer therapy.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.49-54
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• 2014

Background: Hydrogels are a class of polymers that can absorb water or biological fluids and swell to several times their dry volume, dependent on changes in the external environment. In recent years, hydrogels and hydrogel nanocomposites have found a variety of biomedical applications, including drug delivery and cancer treatment. The incorporation of nanoparticulates into a hydrogel matrix can result in unique material characteristics such as enhanced mechanical properties, swelling response, and capability of remote controlled actuation. Materials and Methods: In this work, synthesis of hydrogel nanocomposites containing magnetic nanoparticles are studied. At first, magnetic nanoparticles ($Fe_3O_4$) with an average size 10 nm were prepared. At second approach, thermo and pH-sensitive poly (N-isopropylacrylamide -co-methacrylic acid-co-vinyl pyrrolidone) (NIPAAm-MAA-VP) were prepared. Swelling behavior of co-polymer was studied in buffer solutions with different pH values (pH=5.8, pH=7.4) at $37^{\circ}C$. Magnetic iron oxide nanoparticles ($Fe_3O_4$) and doxorubicin were incorporated into copolymer and drug loading was studied. The release of drug, carried out at different pH and temperatures. Finally, chemical composition, magnetic properties and morphology of doxorubicin-loaded magnetic hydrogel nanocomposites were analyzed by FT- IR, vibrating sample magnetometry (VSM), scanning electron microscopy (SEM). Results: The results indicated that drug loading efficiency was increased by increasing the drug ratio to polymer. Doxorubicin was released more at $40^{\circ}C$ and in acidic pH compared to that $37^{\circ}C$ and basic pH. Conclusions: This study suggested that the poly (NIPAAm-MAA-VP) magnetic hydrogel nanocomposite could be an effective carrier for targeting drug delivery systems of anti-cancer drugs due to its temperature sensitive properties.

• 대한방사성의약품학회지
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• 제1권1호
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• pp.38-45
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• 2015

Most tumors are believed to overexpress several receptors, and small peptides targeting these receptors were developed for diagnosis and tumor therapy during past decade. Here we report that fibroadenoma can be visualized by bladder cancer specific peptide. A 9-mer bladder cancer specific peptide, which was discovered from the phage display method, was synthesized by peptide synthesizer, and additional tyrosine was conjugated at the N-terminal for radioiodination (Y-BP). Y-BP was radiolabeled with $^{131/124}I$ using Iodogen tube. The rat treated with N-butyl-N-(4-hydroxybutyl)nitrosamine for 8 weeks was allowed to grow until large size tumor was developed under axilla. The tumor model was microPET imaged sequentially using [$^{18}F$]FDG and radioiodinated $^{124}I-Y-BP$. The tumor was excised and examined by immunostaining studies. Radioiodinated $^{124}I-Y-BP$ was purified using fast protein liquid chromatography (FPLC) in > 90% radiochemical purity. The whole tumor was well visualized by [$^{18}F$]FDG with several intense focal uptake within tumor. The tumor was also clearly seen with $^{124}I-Y-BP$ at 4 h post-injection, and to our surprise the tumor uptake of $^{124}I-Y-BP$ lasted up to three days. The tumor was diagnosed histologically as a fibroadenoma derived from mammary gland. In conclusion, the bladder cancer specific peptide showed the good potential as a new radiotracer for the detection of breast fibroadenoma.

• Molecules and Cells
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• 제42권3호
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• pp.270-283
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• 2019

This study was aimed to explore if lncRNA MALAT1 would modify chemo-resistance of non-small cell lung cancer (NSCLC) cells by regulating miR-197-3p and p120 catenin (p120-ctn). Within this investigation, we totally recruited 326 lung cancer patients, and purchased 4 NSCLC cell lines of A549, H1299, SPC-A-1 and H460. Moreover, cisplatin, adriamycin, gefitinib and paclitaxel were arranged as chemotherapies, and half maximal inhibitory concentration (IC50) values were calculated to evaluate the chemo-resistance of the cells. Furthermore, mice models of NSCLC were also established to assess the impacts of MALAT1, miR-197-3p and p120-ctn on tumor growth. Our results indicated that MALAT1 and miR-197-3p were both over-expressed within NSCLC tissues and cells, when compared with normal tissues and cells (P < 0.05). The A549, H460, SPC-A-1 and SPC-A-1 displayed maximum resistances to cisplatin ($IC50=15.70{\mu}g/ml$), adriamycin ($IC50=5.58{\mu}g/ml$), gefitinib ($96.82{\mu}mol/L$) and paclitaxel (141.97 nmol/L). Over-expression of MALAT1 and miR-197-3p, or under-expression of p120-ctn were associated with promoted viability and growth of the cancer cells (P < 0.05), and they could significantly strengthen the chemo-resistance of cancer cells (P < 0.05). MALAT1 Wt or p120-ctn Wt co-transfected with miR-197-3p mimic was observed with significantly reduced luciferase activity within NSCLC cells (P < 0.05). Finally, the NSCLC mice models were observed with larger tumor size and weight under circumstances of over-expressed MALAT1 and miR-197-3p, or under-expressed p120-ctn (P < 0.05). In conclusion, MALAT1 could alter chemo-resistance of NSCLC cells by targeting miR-197-3p and regulating p120-ctn expression, which might assist in improvement of chemo-therapies for NSCLC.

• 생명과학회지
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• 제32권1호
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• pp.63-69
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• 2022

Thioredoxin reductase (TrxR) 시스템은 세포 내 산화 환원 반응의 항상성 유지와 신호 전달 경로를 조절하는데 중추적인 역할을 함으로써 세포의 생존과 기능 유지에 필수적이다. TrxR 시스템은 thioredoxin (Trx), TrxR 및 nicotinamide adenine dinucleotide phosphate의 구성요소를 포함하며, TrxR 효소의 촉매 반응에 의해 환원된 Trx는 하위 표적 단백질을 환원시켜 결과적으로 산화적 스트레스에 대한 방어와 세포 분화, 성장 및 사멸을 조절한다. 암세포는 무한한 세포 증식과 높은 대사율로 인해 과도하게 생성된 활성산소종을 소거하기 위해 세포 내 항산화능을 향상시켜 세포의 생존을 유지하는 반면, 항산화 시스템에 대한 의존도 및 민감도가 높아 이를 표적으로 한 항암 활성 연구에서 잠재적인 가능성이 있음을 제시한다. 여러 연구 결과에서 TrxR이 다양한 유형의 암에서 높은 수준으로 발현되고 있음이 밝혀졌고, 또한 TrxR 시스템을 표적으로 한 항암 활성에 대한 연구가 증가하고 있다. 따라서 본 총설에서는 세포 내 TrxR 시스템의 기능과 암의 발달 및 진행에서의 역할을 다루고, TrxR 억제제의 항암 활성 및 기전을 검토함으로써 항암 활성 연구에 대한 전략으로 TrxR 시스템의 타당성과 가치를 논하였다.

• Radiation Oncology Journal
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• 제22권2호
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• pp.77-90
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• 2004

종양 발생 과정에 관여되고 있는 분자 생물학적 기전을 직접 공격해 보자고 하는 치료 방침은 암 치료에 있어서 아주 유망한 치료방법의 하나로 인정되고 있다. Epidermal growth factor receptor (EGFR) 수용체에 여러 ligands가 결합하게 되면 발암 단계에서부터 암의 진행 과정과 전이 과정 그리고 방사선에 대한 저항성과 관련된 여러 가지중요한 신호전달체계를 활성화시킨다. 특히 진행된 두경부 암 환자들에서 EGFR이 과발현 된 경우에는 매우 불량한 예후를 나타내고 있기 때문에 이러한 signaling pathway의 selective targeting을 위한 많은 임상 시도가 이루어지고 있다. 현재까지 알려진 표적치료 항암제로는 크게 EGFR에 대한 monoclonal antibody와 tyrosin kinase Inhibitors로 대별될 수 있는데 이와 같은 약제들은 여러 xenograft에서 고무적인 실험 결과들이 입증되어 곧 바로 임상 현장에서 적용되고 있다. 그러나 기대와는 달리 EGFR Inhibitor 단독으로 치료한 초기 임상연구 결과들을 보면 극히 소수의 환자에서만 미미한 효과를 나타내고 있고, 방사선 치료와의 병용치료에서도 괄목할만한 항암 효과를 보여주지 않고 있다. 그럼에도 불구하고 많은 실험적 데이터로부터 여러 가지 생물학적 이점이 밝혀져 있고 또 미래 지향적인 치료법의 하나로 각광을 받고 있기 때문에 현재 많은 연구자들은 어떤 환자 군에서 이러한 표적 치료가 도움이 될 것이며, 방사선 치료 또는 항암 치료와는 어떤 방식으로 조합할 것인지, 또 그 순서는 어떻게 할 것이며, 또 환자 선정에 있어 reliable marker는 무엇인지, 어떻게 체내에서 신호 전달체계의 효과적인 차단을 확인할 수 있겠는지, 또한 multiple targ리ed therapy가 필 요하도록 하는 targeted agent에 대 한 Intrinsic 또는 acquired resistance의 기전은 무엇인지 등등, 현재 당면하고 있는 많은 문제점을 규명하고자 노력하고 있다. 특히 EGFR-signaling pathway를 표적으로 하는 표적 지향적 방사선 치료를 위한 translation research의 적절한 모델이 되고 있는 두경부 암 환자에서 이러한 제반 문제점을 해결하기 위해서는 더 많은 임상 연구와 함께 well-Integrated laboratory clinical research program이 필요할 것으로 생각된다 또한 EGFR antagonist 외에도 anglogenlc pathway나 cell-cycle pathway를 표적으로 하는 새로운 약제들이 계속 개발되고 있고 이에 관한 연구가 활발히 진행 중이다. 따라서 이 고찰에서는 두경부 암 환자에서 이러한 약제들을 방사선 치료와 병용하였을 때의 임상 연구 결과들을 재검토해 보고 부가적으로 EGFR blockade에 따르는 내성 문제 그리고 방사선 치료를 병용하면서 여러 표적을 동시에 차단시키는 multiple-targeted therapy의 개발 현황을 간략히 소개하고자 한다

• Asian Pacific Journal of Cancer Prevention
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• 제17권10호
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• pp.4609-4614
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• 2016

Purpose: To evaluate the therapeutic effects of copper reduction on angiogenesis-related factors in patients with glioblastoma multiforme treated by gamma knife radiosurgery. Materials and Methods: In the present block randomized, placebo-controlled trial, fifty eligible patients with a diagnosis of glioblastoma multiforme who were candidates for gamma knife radiosurgery were randomly assigned into two groups to receive daily either 1gr penicillamine and a low copper diet or placebo for three months. The intervention started on the same day as gamma knife radiosurgery. Serum interleukin-6 (IL-6), tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), vascular endothelial growth factor (VEGF) and copper levels were measured at baseline and after the intervention. The serum copper level was used as the final index of compliance with the diet. In order to control probable side effects of intervention, laboratory tests were conducted at the beginning, middle and end of the study. Results: The patients had a mean age and Karnofsky Performance Scale of 43.7 years and 75 respectively. Mean serum copper levels were significantly reduced in intervention group. Mean survival time was 18.5 months in intervention group vs. 14.9 in placebo group. VEGF and IL-6 levels in the intervention group were also significantly reduced compared to the placebo group and $TNF-{\alpha}$ increased less. Conclusions: It seems that reducing the level of copper in the diet and dosing with penicillamine leads to decline of angiogenesis-related factors such as VEGF, IL-6 and $TNF-{\alpha}$. Approaches targeting angiogenesis may improve survival and can be used as a future therapeutic strategy.

• 동의생리병리학회지
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• 제18권6호
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• pp.1613-1616
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• 2004

The cellular response to hypoxia is controlled to a large degree by the transcription factor Hypoxia-inducible factor-1(HIF-1). HIF-1 is a transcription factor that is activated by hypoxia and plays a critical role in the development of the cancer phenotype. HIF-1 regulates transcription of a number of genes crucial for tumor survival under hypoxic conditions, including vascular endothelial growth factor(VEGF), erythropoietin(Epo) and several glycolytic enzymes. Tumors in which hypoxia can not induce HIF-1 transcriptional activity remain small and fail to metastasize. In this study, we examined whether aqueous root extract of Ailanthus altissima (REA) downregulate HIF-1, VEGF and p53, and raise the possibility that depletion of these proteins and the anti proliferative activities of REA have any effects on inhibition of angiogenesis in MCF-7 cells. Pharmacologic targeting of specific signal transduction pathways related to oncogenic transformation is a promising approach in cancer treatment. Therefore, REA could be a candidate drug for further clinical development.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2503-2509
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• 2012

Considerable research has been conducted concerning galectin-9 and carcinomas, but little information is available about any relation with the hepatocellular carcinoma. In this study, we employed a small interfering RNA (siRNA) targeting galectin-9 to down-regulate the expression in HepG2 cells. As a result, after galectin-9 expression was reduced, cell aggregation was suppressed, while other behaviour such as the proliferation, adhesion and invasion to ECM, cell-endothelial adhesion and transendothelial invasion of the cells were markedly enhanced. When tumors of 200 patients with hepatocellular carcinoma were tested for galectin-9 expression by immunohistochemistry, binding levels demonstrated intimate correlations with the histopathologic grade, lymph node metastasis, vascular invasion and intrahepatic metastasis (P<0.05). Moreover, survival analysis indicated that patients with galectin-9 expression had much longer survival time than those with negative lesions, and the Log-rank test indicated that this difference was statistical significant (P<0.0001). The Cox proportional hazards model suggested that negative galectin-9 expression in hepatocellular carcinoma represented a significant risk factor for patient survival. We propose that galectin-9 might be a new prognostic factor with antimetastatic potential in patients with hepatocellular carcinoma.